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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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Gumpper-Fedus K, Chasser K, Pita-Grisanti V, Torok M, Pfau T, Mace TA, Cole RM, Belury MA, Culp S, Hart PA, Krishna SG, Lara LF, Ramsey ML, Fisher W, Fogel EL, Forsmark CE, Li L, Pandol S, Park WG, Serrano J, Van Den Eeden SK, Vege SS, Yadav D, Conwell DL, Cruz-Monserrate Z. Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study. Clin Transl Gastroenterol 2024; 15:e00686. [PMID: 38284831 PMCID: PMC11042777 DOI: 10.14309/ctg.0000000000000686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/19/2024] [Indexed: 01/30/2024] Open
Abstract
INTRODUCTION Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.
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Affiliation(s)
- Kristyn Gumpper-Fedus
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Kaylin Chasser
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Valentina Pita-Grisanti
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The Ohio State University Interdisciplinary Nutrition Program, The Ohio State University, Columbus, Ohio, USA
| | - Molly Torok
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Timothy Pfau
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Thomas A. Mace
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Rachel M. Cole
- Department of Food Science and Technology, College of Food, Agriculture, and Environmental Sciences, The Ohio State University Columbus, Ohio, USA
| | - Martha A. Belury
- Department of Food Science and Technology, College of Food, Agriculture, and Environmental Sciences, The Ohio State University Columbus, Ohio, USA
| | - Stacey Culp
- Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Luis F. Lara
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Mitchell L. Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - William Fisher
- Division of General Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Evan L. Fogel
- Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Chris E. Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, USA
| | - Liang Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Stephen Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Walter G. Park
- Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, California, USA
| | - Jose Serrano
- Division of Digestive Diseases and Nutrition, National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | | | - Santhi Swaroop Vege
- Department of Gastroenterology and Hepatology, The Mayo Clinic, Rochester, Minnesota, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology & Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Darwin L. Conwell
- Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
- The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Lee B, Jones EK, Manohar M, Li L, Yadav D, Conwell DL, Hart PA, Vege SS, Fogel EL, Serrano J, Andersen D, Bellin MD, Topazian MD, Van Den Eeden SK, Pandol SJ, Forsmark CE, Fisher WE, Park WG, Husain SZ, Habtezion A. Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study. Gastroenterology 2023; 165:173-186. [PMID: 37061168 PMCID: PMC10330331 DOI: 10.1053/j.gastro.2023.03.236] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 03/21/2023] [Accepted: 03/30/2023] [Indexed: 04/17/2023]
Abstract
BACKGROUND & AIMS Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.
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Affiliation(s)
- Bomi Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, School of Medicine, Stanford University, Stanford, California.
| | - Elaina K Jones
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, School of Medicine, Stanford University, Stanford, California
| | - Murli Manohar
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, School of Medicine, Stanford University, Stanford, California
| | - Liang Li
- Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Darwin L Conwell
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Santhi Swaroop Vege
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Evan L Fogel
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jose Serrano
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Dana Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Melena D Bellin
- Division of Pediatric Endocrinology, University of Minnesota, Minneapolis, Minnesota
| | - Mark D Topazian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Stephen J Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California
| | - Chris E Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida
| | - William E Fisher
- Division of General Surgery, Baylor College of Medicine, Houston, Texas
| | - Walter G Park
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Sohail Z Husain
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, School of Medicine, Stanford University, Stanford, California
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
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Zheng M, Gao R. Vitamin D: A Potential Star for Treating Chronic Pancreatitis. Front Pharmacol 2022; 13:902639. [PMID: 35734414 PMCID: PMC9207250 DOI: 10.3389/fphar.2022.902639] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas. The incidence of CP is increasing worldwide but the effective therapies are lacking. Hence, it is necessary to identify economical and effective agents for the treatment of CP patients. Vitamin D (VD) and its analogues have been confirmed as pleiotropic regulators of cell proliferation, apoptosis, differentiation and autophagy. Clinical studies show that VD deficiency is prevalent in CP patients. However, the correlation between VD level and the risk of CP remains controversial. VD and its analogues have been demonstrated to inhibit pancreatic fibrosis by suppressing the activation of pancreatic stellate cells and the production of extracellular matrix. Limited clinical trials have shown that the supplement of VD can improve VD deficiency in patients with CP, suggesting a potential therapeutic value of VD in CP. However, the mechanisms by which VD and its analogues inhibit pancreatic fibrosis have not been fully elucidated. We are reviewing the current literature concerning the risk factors for developing CP, prevalence of VD deficiency in CP, mechanisms of VD action in PSC-mediated fibrogenesis during the development of CP and potential therapeutic applications of VD and its analogues in the treatment of CP.
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Palathingal Bava E, George J, Iyer S, Sahay P, Tarique M, Jain T, Vaish U, Giri B, Sharma P, Saluja AK, Dawra RK, Dudeja V. Pirfenidone ameliorates chronic pancreatitis in mouse models through immune and cytokine modulation. Pancreatology 2022; 22:553-563. [PMID: 35570091 DOI: 10.1016/j.pan.2022.05.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 04/30/2022] [Accepted: 05/03/2022] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis (CP) is an irreversible fibro-inflammatory disease of the pancreas with no current targeted therapy. Pirfenidone, an anti-fibrotic and anti-inflammatory drug, is FDA approved for treatment of Idiopathic Pulmonary Fibrosis (IPF). Its efficacy in ameliorating CP has never been evaluated before. We recently reported that pirfenidone improves acute pancreatitis in mouse models. The aim of the current study was to evaluate the therapeutic efficacy of pirfenidone in mouse models of CP. We used caerulein and L-arginine models of CP and administered pirfenidone with ongoing injury, or in well-established disease. We evaluated for fibrosis by Sirius-red staining for collagen, immunohistochemistry, western blotting, and qPCR for fibrosis markers to show the salutary effects of pirfenidone in CP. Our results suggest that treatment with pirfenidone ameliorated CP related changes in the pancreas (i.e., atrophy, acinar cell loss, fibrosis, and inflammation) not only when administered with ongoing injury, but also in well-established models of caerulein as well as L-arginine induced CP. It reduces the pro-fibrotic phenotype of macrophages (in-vivo and in-vitro), reduces macrophage infiltration into the pancreas and alters the intra-pancreatic cytokine milieu preceding changes in histology. The therapeutic effect of pirfenidone is abrogated in absence of macrophages. Furthermore, it reduces collagen secretion, cytokine levels and fibrosis markers in pancreatic stellate cells in-vitro. As it is FDA approved, our findings in mouse models simulating clinical presentation of patients to the clinic, can be used as the basis of a clinical trial evaluating the efficacy of this drug as a therapeutic agent for CP.
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Affiliation(s)
| | - John George
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Srikanth Iyer
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Preeti Sahay
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mohammad Tarique
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Tejeshwar Jain
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Utpreksha Vaish
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Bhuwan Giri
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Prateek Sharma
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ashok K Saluja
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Rajinder K Dawra
- Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham Veteran Affairs Medical Center, Birmingham, AL, USA.
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Tao X, Xiang H, Pan Y, Shang D, Guo J, Gao G, Xiao GG. Pancreatitis initiated pancreatic ductal adenocarcinoma: Pathophysiology explaining clinical evidence. Pharmacol Res 2021; 168:105595. [PMID: 33823219 DOI: 10.1016/j.phrs.2021.105595] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/04/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant lethal disease due to its asymptomatic at its early lesion of the disease and drug resistance. Target therapy associated with molecular pathways so far seems not to produce reasonable outcomes. Understanding of the molecular mechanisms underlying inflammation-initiated tumorigenesis may be helpful for development of an effective therapy of the disease. A line of studies showed that pancreatic tumorigenesis was resulted from pancreatitis, which was caused synergistically by various pancreatic cells. This review focuses on those players and their possible clinic implications, such as exocrine acinar cells, ductal cells, and various stromal cells, including pancreatic stellate cells (PSCs), macrophages, lymphocytes, neutrophils, mast cells, adipocytes and endothelial cells, working together with each other in an inflammation-mediated microenvironment governed by a myriad of cellular signaling networks towards PDAC.
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Affiliation(s)
- Xufeng Tao
- Department of Pharmacology at School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Hong Xiang
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yue Pan
- Department of Pharmacology at School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Dong Shang
- Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Junchao Guo
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ge Gao
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Gary Guishan Xiao
- Department of Pharmacology at School of Chemical Engineering, Dalian University of Technology, Dalian, China; The UCLA Agi Hirshberg Center for Pancreatic Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Functional Genomics and Proteomics Laboratory, Osteoporosis Research Center, Creighton University Medical Center, Omaha, NE, United States.
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Lee B, Adamska JZ, Namkoong H, Bellin MD, Wilhelm J, Szot GL, Louis DM, Davis MM, Pandol SJ, Habtezion A. Distinct immune characteristics distinguish hereditary and idiopathic chronic pancreatitis. J Clin Invest 2021; 130:2705-2711. [PMID: 32053120 DOI: 10.1172/jci134066] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/11/2020] [Indexed: 01/03/2023] Open
Abstract
Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients including those with hereditary and idiopathic CP undergoing total pancreatectomy with islet autotransplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP samples showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in the CP and control groups. TCRβ sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreases indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanisms of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis, providing insights into immune responses associated with human CP.
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Affiliation(s)
- Bomi Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical School, Stanford, California, USA
| | - Julia Z Adamska
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical School, Stanford, California, USA
| | - Hong Namkoong
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical School, Stanford, California, USA
| | - Melena D Bellin
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota Medical Center, Minneapolis, Minnesota, USA.,Department of Pediatrics, University of Minnesota Medical Center and Masonic Children's Hospital, Minneapolis, Minnesota, USA
| | - Josh Wilhelm
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
| | - Gregory L Szot
- Division of Transplantation, Department of Surgery, UCSF, San Francisco, California, USA
| | | | - Mark M Davis
- Department of Microbiology and Immunology.,Institute for Immunity, Transplantation and Infection, and.,Howard Hughes Medical Institute (HHMI), Stanford University Medical School, Stanford, California, USA
| | - Stephen J Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical School, Stanford, California, USA.,Institute for Immunity, Transplantation and Infection, and
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Mukherjee D, DiVincenzo MJ, Torok M, Choueiry F, Kumar RJ, Deems A, Miller JL, Hinton A, Geraghty C, Maranon JA, Kulp SK, Coss C, Carson WE, Conwell DL, Hart PA, Cooperstone JL, Mace TA. Soy-tomato enriched diet reduces inflammation and disease severity in a pre-clinical model of chronic pancreatitis. Sci Rep 2020; 10:21824. [PMID: 33311549 PMCID: PMC7733503 DOI: 10.1038/s41598-020-78762-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 μg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP (p = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels (p < 0.05). Mice with CP fed a soy-tomato diet had a reduction in inflammatory factors (TNF-α, IL-1β, IL-5) and suppressive immune populations (myeloid-derived suppressor cells; MDSC) compared to control diet fed mice (p < 0.05). Infra-red sensing to monitor spontaneous activity of mice showed that soy-tomato enriched diet improved total activity and overall health of mice with CP (p = 0.055) and CP mice on a control diet were determined to spend more time at rest (p = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.
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Affiliation(s)
| | - Mallory J DiVincenzo
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
- Department of Veterinary Biosciences, The Ohio State University, Columbus, USA
| | - Molly Torok
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Fouad Choueiry
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Rahul J Kumar
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Anna Deems
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | - Jenna L Miller
- Department of Food Science and Technology, The Ohio State University, Columbus, USA
| | - Alice Hinton
- Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, USA
| | - Connor Geraghty
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA
| | | | - Samuel K Kulp
- College of Pharmacy, The Ohio State University, Columbus, USA
| | | | | | - Darwin L Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 420 W 12th Ave., Columbus, OH, 43210, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 420 W 12th Ave., Columbus, OH, 43210, USA
| | - Jessica L Cooperstone
- Department of Food Science and Technology, The Ohio State University, Columbus, USA
- Departments of Horticulture and Crop Science, The Ohio State University, Columbus, OH, 43210, USA
| | - Thomas A Mace
- James Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, 420 W 12th Ave., Columbus, OH, 43210, USA.
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Role of the Immune System and the Circadian Rhythm in the Pathogenesis of Chronic Pancreatitis: Establishing a Personalized Signature for Improving the Effect of Immunotherapies for Chronic Pancreatitis. Pancreas 2020; 49:1024-1032. [PMID: 32833942 DOI: 10.1097/mpa.0000000000001626] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatitis, in both acute and chronic forms, poses a major therapeutic challenge and is associated with great morbidity and several complications. The nature of pancreatic injury in chronic pancreatitis (CP) and the wide range of causative processes that lead to CP have made effective therapy a true unmet need. Multiple physiological, genetic, environmental, and behavioral factors contribute to the development of CP. As a result, several fields of research are aimed at identifying and addressing the factors that contribute to pancreatic injury. In this article, we review the current understanding of the pathogenesis and natural history of CP. We focus on the autonomous nervous system, immune system, and role of a chronobiological therapeutic approach to alleviate symptoms and prevent or reverse pancreatic injury associated with CP. We aim to demonstrate that individualizing chronopharmacological treatments for CP is a promising direction for future treatment using immune, nervous, and circadian systems.
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Alcohol and Smoking Mediated Modulations in Adaptive Immunity in Pancreatitis. Cells 2020; 9:cells9081880. [PMID: 32796685 PMCID: PMC7463831 DOI: 10.3390/cells9081880] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatitis is a condition of pancreatic inflammation driven by injury to the pancreatic parenchyma. The extent of acinar insult, intensity, and type of immune response determines the severity of the disease. Smoking, alcohol and autoimmune pancreatitis are some of the predominant risk factors that increase the risk of pancreatitis by differentially influencing the adaptive immune system. The overall decrease in peripheral lymphocyte (T-, B- and (natural killer T-) NKT-cell) count and increased infiltration into the damaged pancreatic tissue highlight the contribution of adaptive immunity in the disease pathology. Smoking and alcohol modulate the responsiveness and apoptosis of T- and B-cells during pancreatic insult. Acute pancreatitis worsens with smoking and alcohol, leading to the development of systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome, suggesting the critical role of adaptive immunity in fatal outcomes such as multiple organ dysfunction. The presence of CD4+ and CD8+ T-lymphocytes and perforin-expressing cells in the fibrotic tissue in chronic pancreatitis modulate the severity of the disease. Due to their important role in altering the severity of the disease, attempts to target adaptive immune mediators will be critical for the development of novel therapeutic interventions.
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Gumpper K, Dangel AW, Pita-Grisanti V, Krishna SG, Lara LF, Mace T, Papachristou GI, Conwell DL, Hart PA, Cruz-Monserrate Z. Lipocalin-2 expression and function in pancreatic diseases. Pancreatology 2020; 20:419-424. [PMID: 31932215 PMCID: PMC7160010 DOI: 10.1016/j.pan.2020.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/31/2019] [Accepted: 01/03/2020] [Indexed: 02/08/2023]
Abstract
Lipocalin-2 (LCN2) is a secreted molecule, expressed in various cell types, that is involved in the progression of numerous diseases and disorders. The biological functions and expression levels of LCN2 in diseases including pancreatic cancer, pancreatitis (acute and chronic), and diabetes mellitus, suggest the potential role of LCN2 as a biomarker and/or therapeutic target. However, findings on the role of LCN2 in pancreatic diseases have been contradictory. In pancreatic cancer and pancreatitis, LCN2 has been identified as a potential biomarker; increased expression levels in various biological specimens correlate with the presence of the disease and may be able to differentiate cancer and chronic pancreatitis from healthy subjects. LCN2 is also known to be an adipokine; it is upregulated in obesity and is a common co-factor in the development of pancreatic diseases. Emerging research suggests LCN2 is elevated in type 2 diabetes mellitus, but the exact role of LCN2 in this disease is not clear. In this review, we summarize research on LCN2 as it relates to pancreatic diseases, highlighting the discrepancies in the literature. By explaining and clarifying the role of LCN2 in these disorders, we aim to promote research in developing novel diagnostic and treatment strategies to reduce the burden of pancreatic diseases.
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Affiliation(s)
- Kristyn Gumpper
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Andrew William Dangel
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Valentina Pita-Grisanti
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Somashekar G Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Luis F Lara
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Thomas Mace
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Georgios I Papachristou
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Darwin L Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas. The currently available treatment of CP is aimed at controlling symptoms and managing complications. Unfortunately, no specific treatment is available to halt the progression of the disease process because the pathophysiological perturbations in CP are not well understood. In this review, we discuss various therapeutic targets and investigational agents acting on these targets. Among these, therapies modulating immune cells and those acting on pancreatic stellate cells appear promising and may translate into clinical benefit in near future. However, these experimental therapies are mostly in animal models and they do not recapitulate all aspects of human disease. Still they may be beneficial in developing effective therapeutic modalities to curb inflammation in chronic pancreatitis.
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Klieser E, Swierczynski S, Mayr C, Jäger T, Schmidt J, Neureiter D, Kiesslich T, Illig R. Differential role of Hedgehog signaling in human pancreatic (patho-) physiology: An up to date review. World J Gastrointest Pathophysiol 2016; 7:199-210. [PMID: 27190692 PMCID: PMC4867399 DOI: 10.4291/wjgp.v7.i2.199] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 10/21/2015] [Accepted: 03/09/2016] [Indexed: 02/06/2023] Open
Abstract
Since the discovery of the Hedgehog (Hh) pathway in drosophila melanogaster, our knowledge of the role of Hh in embryonic development, inflammation, and cancerogenesis in humans has dramatically increased over the last decades. This is the case especially concerning the pancreas, however, real therapeutic breakthroughs are missing until now. In general, Hh signaling is essential for pancreatic organogenesis, development, and tissue maturation. In the case of acute pancreatitis, Hh has a protective role, whereas in chronic pancreatitis, Hh interacts with pancreatic stellate cells, leading to destructive parenchym fibrosis and atrophy, as well as to irregular tissue remodeling with potency of initiating cancerogenesis. In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment. The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials (phases 1 and 2). Furthermore, a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach. In this review, we give a structured survey of the role of the Hh pathway in pancreatic development, pancreatitis, pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.
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Klieser E, Swierczynski S, Mayr C, Schmidt J, Neureiter D, Kiesslich T, Illig R. Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy. World J Gastrointest Oncol 2015; 7:473-483. [PMID: 26691388 PMCID: PMC4678394 DOI: 10.4251/wjgo.v7.i12.473] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 09/03/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis (AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future therapies. Histone deacetylases (HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcription. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.
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Abstract
Alcohol and gallstones are the most common etiologic factors in acute pancreatitis (AP). Recurrent AP can lead to chronic pancreatitis (CP). Although the underlying pathophysiology of the disease is complex, immune cells are critical in the pathogenesis of pancreatitis and determining disease severity. In this review, we discuss the role of innate and adaptive immune cells in both AP and CP, potential immune-based therapeutic targets, and animal models used to understand our knowledge of the disease. The relative difficulty of obtaining human pancreatic tissue during pancreatitis makes animal models necessary. Animal models of pancreatitis have been generated to understand disease pathogenesis, test therapeutic interventions, and investigate immune responses. Although current animal models do not recapitulate all aspects of human disease, until better models can be developed available models are useful in addressing key research questions. Differences between experimental and clinical pancreatitis need consideration, and when therapies are tested, models with established disease ought to be included.
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Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol 2014; 20:11160-11181. [PMID: 25170202 PMCID: PMC4145756 DOI: 10.3748/wjg.v20.i32.11160] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/27/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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Zheng L, Xue J, Jaffee EM, Habtezion A. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 2013; 144:1230-40. [PMID: 23622132 PMCID: PMC3641650 DOI: 10.1053/j.gastro.2012.12.042] [Citation(s) in RCA: 249] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/12/2012] [Accepted: 12/21/2013] [Indexed: 12/22/2022]
Abstract
Immune cells are important in the pathogenesis of acute pancreatitis and determine disease severity. Results from cytokine-based clinical trials for acute pancreatitis have been disappointing, so strategies that target and alter the behavior of infiltrating immune cells require consideration. Recurrent acute pancreatitis can progress to chronic pancreatitis, which is a well-described risk factor for pancreatic ductal adenocarcinoma (PDA). However, most patients with chronic pancreatitis do not develop PDA, and most patients with PDA do not have a history of pancreatitis. Interestingly, chronic pancreatitis and PDA tissues have similarities in their desmoplasia and inflammatory infiltrates, indicating overlapping inflammatory responses. Further studies are needed to determine the differences and similarities of these responses, improve our understanding of PDA pathogenesis, and develop specific immune-based therapies. Immune cells in PDA produce immunosuppressive signals that allow tumors to evade the immune response. Unlike single therapeutic agent studies that block immunosuppressive mechanisms, studies of combination therapies that include therapeutic vaccines have provided promising results.
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Affiliation(s)
- Lei Zheng
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jing Xue
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elizabeth M. Jaffee
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Aida Habtezion
- Stanford University School of Medicine, Department of Medicine, Division of Gastroenterology and Hepatology, Stanford, California and The Sidney Kimmel Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Changes in 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D are associated with maturation of regulatory T lymphocytes in patients with chronic pancreatitis: a randomized controlled trial. Pancreas 2012; 41:1213-8. [PMID: 22695134 DOI: 10.1097/mpa.0b013e31824da377] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES We studied the impact of changes in 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) on regulatory T lymphocytes (Tregs) in patients with chronic pancreatitis (CP) and fat malabsorption in a prospective clinical trial. METHODS The patients were randomized to 1 of 3 treatments during 10 weeks: weekly UV-B in a tanning bed (group A), 1520-IU/d vitamin D supplement (group B), or placebo (group C). A placebo tanning bed was used in groups B and C. We determined the levels of CD4 Tregs (CD3(+)CD4(+)CD25(+)CD127(low)FoxP3(+)) and CD8(+) Tregs (CD3(+)CD8(+)CD25(+)CD127(low)FoxP3(+)), together with 25OHD and 1,25(OH)2D. For baseline comparisons, we included 8 healthy individuals. Of the 30 included patients, 27 (group A, 7 patients; group B, 9 patients; and group C, 11 patients) completed the protocol. RESULTS The baseline levels of CD4(+) Tregs relative to total CD4(+) count were higher in 22 patients with CP compared with healthy controls (2.8% vs 1.9%, P < 0.05) and were comparable for CD8+ Tregs (0.13% vs 0.05%, P = 0.3). Increases in levels of CD4(+) Tregs correlated to changes in 1,25(OH)(2)D (2% per 100 pmol/L, P = 0.002) and 25OHD (3% per 100 nmol/L, P = 0.01). CONCLUSIONS Patients with CP have elevated relative levels of CD4(+) Tregs. Increases in 25OHD and 1,25(OH)(2)D were both related with increases in levels of Tregs.
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Schmitz-Winnenthal H, Pietsch DHK, Schimmack S, Bonertz A, Udonta F, Ge Y, Galindo L, Specht S, Volk C, Zgraggen K, Koch M, Büchler MW, Weitz J, Beckhove P. Chronic pancreatitis is associated with disease-specific regulatory T-cell responses. Gastroenterology 2010; 138:1178-88. [PMID: 19931255 DOI: 10.1053/j.gastro.2009.11.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2008] [Revised: 10/20/2009] [Accepted: 11/09/2009] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Chronic pancreatitis is characterized by alternating phases of acute inflammation and quiescent disease. Involvement of T-cell responses has been suggested, but pancreatitis-specific T cells have not been described. METHODS We characterized T-cell responses against pancreatitis, pancreatic carcinoma-associated antigens, and tetanus toxoid in the bone marrow, blood, and/or pancreatitis lesions of patients with pancreatitis, pancreatic cancer, and healthy individuals. T cells were functionally characterized by antigen-dependent secretion of interferon (IFN)-gamma, interleukin (Il)-4, and IL-10, which indicate type 1, type 2, or regulatory T-cell responses, respectively. Regulatory T cells were characterized by multicolor flow cytometry. Isolated regulatory T cells were tested for their capacity to recognize pancreatitis-associated antigens and to suppress conventional T cells in an antigen-dependent manner. T cell-derived cytokines in tissue lesions were quantified by enzyme-linked immunosorbent assay. RESULTS Chronic pancreatitis patients showed similar to pancreatic cancer patients and healthy individuals type 1 T-cell responses against tetanus toxoid; however, they exhibited strong IL-10-based T-cell responses against pancreatitis-associated but not pancreatic carcinoma-associated antigens. T cells from pancreatic cancer patients responded to pancreatic cancer-associated but not pancreatitis-associated antigens with IFN-gamma secretion. Pancreatitis-specific IL-10 responses were mediated by IL-10(+)IFN-gamma(-)FoxP3(+) regulatory T cells, which were expanded in the blood, bone marrow, and pancreatitis lesions and possessed the potential to suppress the proliferation of autologous conventional T cells in an antigen-specific manner. Pancreatitis lesions, in comparison with pancreatic carcinomas, contained increased concentrations of IL-10 and reduced levels of IFN-gamma, suggesting pancreatitis-specific activity of regulatory T cells in situ. CONCLUSIONS Chronic pancreatitis is associated with disease-specific regulatory T-cell responses.
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Michalski CW, Selvaggi F, Bartel M, Mitkus T, Gorbachevski A, Giese T, Sebastiano PD, Giese NA, Friess H. Altered anti-inflammatory response of mononuclear cells to neuropeptide PACAP is associated with deregulation of NF-{kappa}B in chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2008; 294:G50-7. [PMID: 17962362 DOI: 10.1152/ajpgi.00058.2007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although it is recognized that neurogenic influences contribute to progression of chronic inflammatory diseases, the molecular basis of neuroimmune interactions in the pathogenesis of chronic pancreatitis (CP) is not well defined. Here we report that responsiveness of peripheral blood mononuclear cells (PBMC) to the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is altered in CP. Expression of PACAP and its receptors in human CP was analyzed with quantitative RT-PCR, laser-capture microdissection, and immunohistochemistry. Regulation of PACAP expression was studied in coculture systems using macrophages and acinar cells. Responsiveness of donor and CP PBMC to PACAP was determined based on cytokine profiles and NF-kappaB activation of LPS- or LPS+PACAP-exposed cells. Although donor and CP PBMC responded equally to LPS, PACAP-mediated counteraction of LPS-induced cytokine response was switched from inhibiting TNF-alpha to decreasing IL-1beta and increasing IL-10 secretion. The change of PACAP-mediated anti-inflammatory pattern was associated with altered activation of NF-kappaB: compared with LPS alone, a combination of LPS and PACAP had no effect on NF-kappaB p65 nuclear translocation in CP PBMC, whereas NF-kappaB was significantly decreased in donor PBMC. According to laser-capture microdissection and coculture experiments, PBMC also contributed to generation of a PACAP-rich intrapancreatic environment by upregulating PACAP expression in macrophages encountering apoptotic pancreatic acini. The nociceptive status of CP patients correlated with pancreatic PACAP levels and with IL-10 bias of PACAP-exposed CP PBMC. Thus the ability of PBMC to produce and to respond to PACAP might influence neuroimmune interactions that regulate pain and inflammation in CP.
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Affiliation(s)
- Christoph W Michalski
- Dept. of General Surgery, Technische Universität München, Ismaningerstrasse 22, D-86175 Munich, Germany.
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Liu GZ, Fang LB, Hjelmström P, Gao XG. Increased CD8+ central memory T cells in patients with multiple sclerosis. Mult Scler 2007; 13:149-55. [PMID: 17439879 DOI: 10.1177/1352458506069246] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A T-cell-mediated autoimmune process against central nervous system myelin is believed to underlie the pathogenesis of multiple sclerosis (MS). Formation of immunological memory is based on the differentiation of naïve T cells to memory T cells after exposure to antigens and specific cytokines. The aim of this study was to analyse peripheral blood mononuclear cells in patients with MS for different T-cell subsets including naïve and memory T cells. Flow cytometry and enzyme-linked immunosorbent assay were used to analyse memory T-cell subsets and plasma concentration of interleukin-15 (IL-15) in peripheral blood of MS patients, patients with other neurological disorders and healthy controls. MS patients had a skewed distribution of T cells with an increased level of CD8+/CCR7+/CD45RA - central memory T cells (TCM) compared to healthy controls. In addition, MS patients showed significantly higher levels of plasma IL-15 than healthy controls did. Upregulated CD8+ TCM in MS patients may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. This derangement may be important for maintaining chronic inflammation in MS.
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Affiliation(s)
- Guang-Zhi Liu
- Department of Neurology, Peking University People's Hospital, Beijing, PR China.
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Inatomi O, Andoh A, Yagi Y, Ogawa A, Hata K, Shiomi H, Tani T, Takayanagi A, Shimizu N, Fujiyama Y. Matrix metalloproteinase-3 secretion from human pancreatic periacinar myofibroblasts in response to inflammatory mediators. Pancreas 2007; 34:126-32. [PMID: 17198194 DOI: 10.1097/01.mpa.0000246662.23128.57] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Matrix metalloproteinases (MMPs) play roles in the pathophysiology of pancreatic disorders. However, the regulation of MMP-3 secretion in the pancreas remains unclear. In this study, we assessed the expression of MMP-3 in human pancreatic periacinar myofibroblasts. METHODS MMP-3 secretion and MMP-3 mRNA expression were determined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction, respectively. RESULTS In human pancreatic myofibroblasts, MMP-3 secretion and mRNA expression were induced by interleukin (IL)-17, IL-1beta, and tumor necrosis factor (TNF) -alpha, respectively. The effects of IL-17 were detected as similar in extent to those induced by IL-1beta or TNF-alpha. Costimulation by IL-17 plus IL-1beta and/or IL-17 plus TNF-alpha induced a synergistic increase in MMP-3 secretion, although the costimulatory effects of these combinations were not detected in tissue inhibitor of matrix metalloproteinase-1 secretion. Adenovirus-mediated transfer of a stable form of IkappaBalpha markedly inhibited the effects of IL-17, IL-1beta, and TNF-alpha. Mitogen-activated protein kinase inhibitors (U0126, PD098059, and SB203580) also blocked MMP-3 secretion. These findings indicate a role for nuclear factor-kappaB and mitogen-activated protein kinases in cytokine-induced MMP-3 secretion. CONCLUSIONS Pancreatic periacinar myofibroblasts actively secrete MMP-3 in response to IL-17, IL-1beta, and TNF-alpha. Pancreatic myofibroblasts may play an important role in extracellular matrix turnover via MMP-3 secretion in the pancreas.
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Affiliation(s)
- Osamu Inatomi
- Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan
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Fogar P, Sperti C, Basso D, Sanzari MC, Greco E, Davoli C, Navaglia F, Zambon CF, Pasquali C, Venza E, Pedrazzoli S, Plebani M. Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas 2006; 32:22-28. [PMID: 16340740 DOI: 10.1097/01.mpa.0000188305.90290.50] [Citation(s) in RCA: 189] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES An impaired host immunity might concur in determining the dismal prognosis of patients with pancreatic cancer (PC). Our aim was to ascertain whether the immunophenotype pattern of blood lymphocytes in PC correlates with tumor stage, grade, or survival. METHODS We studied 115 patients with PC, 44 with chronic pancreatitis (CP), 23 with tumors of the pancreatico-biliary tract, and 34 healthy controls (CS). Survival data were available for 77 patients with PC. Lymphocyte subsets were determined by fluorescent activated cell sorter (FACS) analysis. RESULTS In patients with PC, total lymphocyte counts were lower than in CP or CS, and CD8 lymphocyte subset levels were higher with respect to CS. Lower circulating lymphocytes were found in advanced PC stages (IIB-IV; chi2 = 11.55, P < 0.05) compared with stages 0 to IIA. Cox regression analysis, made considering total lymphocyte counts and tumor stage as covariates, was found to be significant for both tumor stage (P < 0.001) and total lymphocyte counts (P < 0.05). CONCLUSIONS The reduction of total lymphocytes in blood is the main immunologic change in advanced PC. The survival of these patients depends mainly on tumor stage, but it is also affected by the number of circulating lymphocytes, suggesting that the immune system plays an important role in pancreatic adenocarcinoma immunosurveillance and immunoediting.
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Affiliation(s)
- Paola Fogar
- Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
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